Early Administration of Edoxaban After Acute Ischemic Stroke in Patients With Non-valvular Atrial Fibrillation

December 9, 2020 updated by: Jong Sung Kim

Early Administration of Edoxaban After Acute Ischemic Stroke in Patients With Non-valvular Atrial Fibrillation: a Randomized, Multi-center, Parallel-group Trial (PILOT)

The investigators hypothesize that earlier initiation of edoxaban in AF-related stroke patients may significantly reduce the early recurrence of ischemic stroke, compared with conventional strategy of anticoagulation following 1-3-6-12 rule. To expedite the verification of the hypothesis, the investigators are planning to use diffusion weighted imaging (DWI), which has been reported to be a surrogate to predict both short-term and long-term prognosis after stroke, to detect the recurrent ischemic events. Because data on the early anticoagulation in patients with AF-related stroke are limited, the investigators decided to perform a pilot study before establishing an appropriate clinical trial protocol. This study will help estimate the efficacy and safety of early administration of edoxaban, and determine the sample size of a following clinical trial. To ensure the safety in this pilot exploration, the investigators will not include patients with severe ischemic strokes, who are often prone to experience hemorrhagic transformation in the acute post-stroke period.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

In patients with ischemic stroke and atrial fibrillation (AF), the risk of stroke recurrence is high, especially shortly after the event. Because AF-related strokes are usually larger in their size and more fatal than other types of ischemic stroke, it is important to prevent recurrent cardioembolic strokes with adequate secondary prevention. However, as damaged brain tissues and vessels are prone to bleed, early anticoagulation may be harmful.

For this reason, urgent anticoagulation has not been recommended in stroke patients with AF, and the appropriate time point to start anticoagulation remains controversial. Guideline recommends 1-3-6-12 rule* in initiating anticoagulation. However, this rule is not derived from a scientifically proven study results. Furthermore, although the risk of intracranial hemorrhage may be reduced to some extent with this strategy, the risk of early recurrence of embolic stroke may outweigh the potential benefit of delayed anticoagulation.

Edoxaban, which selectively blocks factor Xa, has a lower risk of hemorrhage, but with a similar efficacy in preventing ischemic events in patients with AF compared with warfarin. Even compared with the other factor Xa inhibitors, it is considered to have a lower risk of bleeding. Therefore, edoxaban may be safely given in the early phase in patients with stroke associated with AF, while not significantly increasing the risk of hemorrhages.

Study Type

Interventional

Enrollment (Actual)

68

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

20 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Acute ischemic strokes (< 48 h from symptom onset) showing ischemic lesions confirmed by DWI, which are attributable to atrial fibrillation
  2. Evidence of persistent or paroxysmal atrial fibrillation (already known or newly detected)
  3. Age ≥20 y
  4. Patients who provided informed consent

Exclusion Criteria:

  1. Transient ischemic attack with no DWI lesions or severe ischemic strokes (NIHSS >16)
  2. Significant hemorrhagic transformation (parenchymal hematoma type I or type II by the ECASS definition or those accompanying with worsening of an existing focal neurological deficit [NIHSS ≥4])10 on baseline MRI
  3. Mechanical heart valve, rheumatic heart valve disease, or any other conditions requiring strong anticoagulation such as vitamin K antagonist or heparin treatment
  4. Concomitant significant atherosclerotic stenosis (>50%) in the proximal arteries, which are possibly responsible for stroke lesions
  5. Recent (<3 months) history of cerebral bleeding
  6. Active internal bleeding or clinically significant bleeding
  7. Severe anemia (Hb <10 g/dL) or bleeding diathesis (platelet count <100,000/uL or PT-INR >1.7) (If there is no active bleeding sign, it is permitted to enroll Hb <9 g/dL , platelet count <70,000/uL)
  8. Uncontrolled hypertension: persistent systolic pressure >180 mmHg or diastolic pressure >110 mmHg
  9. Active, advanced medical diseases (liver, kidney, pulmonary disease or cancer) with a life expectancy <6 months
  10. Renal impairment (CrCl <30 mL/min) or undergoing Hemodialysis (or Peritoneal Dialysis)
  11. Treatment with a strong inducer of p-glycoprotein (carbamazepine, dexamethasone, doxorubicin, nefazodone, pentobarbital, phenobarbital, prazocin, rifampin, St.John's wort, tenofovir, tipranavir, trazodone, vinblastine)
  12. Contraindication to MRI
  13. Pregnancy, breast-feeding or having a plan to be pregnant
  14. Participation in the other investigational drug trials simultaneously or within 3 months before the first administration of the study medication. Observational studies without an intervention (eg study medication) are allowed.
  15. Any clinical conditions (eg abnormal lab tests) unsuitable for undergoing clinical trials at the discretion of the clinical investigators
  16. Known hypersensitivity to the study drug (edoxaban), its ingredients, or formulation excipients
  17. Patient with liver disease related to coagulation disorder and clinically significant bleeding risk
  18. Severe Liver disease

  19. Patient who has increase risk of bleeding due to the following disease

    • recent gastrointestinal ulcer history
    • carcinoma increased risk of bleeding
    • recent brain or spinal injury
    • recent brain, spinal or optical surgery histroy
    • esophageal varix
    • arteriovenous malformations
    • vascular aneurysms (over 3.5cm)
    • intra spinal or cerebral vascular disorder
  20. Patient with other anticoagulants
  21. intermitant or severe mitral stenosis
  22. a pulmonary embolism patient who is hemodynamic unstabled or required thrombolytic therpy or pulmonary emnolectomy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Early edoxaban initiation group
Low dose of edoxaban (15 or 30 mg) once daily from Day 2, then standard dose of edoxaban (30 or 60 mg) according to '3-6' rule.
Drug: Edoxaban

1-3-6-12 rule*

Anticoagulation in patients with acute ischemic stroke and atrial fibrillation can be initiated from the following days after stroke event.

After 1 day: transient ischemic attacks

After 3 days: mild ischemic strokes (NIHSS <8)

After 6 days: moderate ischemic strokes (NIHSS 8-16)

After 12 days: severe ischemic strokes (NIHSS >16)

- NIHSS: National Institute of Health Stroke Scales

Other Names:
  • Lixiana
Active Comparator: Conventional edoxaban initiation group
No antithrombotic treatment† -- then standard dose of edoxaban (30 or 60 mg) according to '3-6' rule.
Drug: Edoxaban

1-3-6-12 rule*

Anticoagulation in patients with acute ischemic stroke and atrial fibrillation can be initiated from the following days after stroke event.

After 1 day: transient ischemic attacks

After 3 days: mild ischemic strokes (NIHSS <8)

After 6 days: moderate ischemic strokes (NIHSS 8-16)

After 12 days: severe ischemic strokes (NIHSS >16)

- NIHSS: National Institute of Health Stroke Scales

Other Names:
  • Lixiana

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
recurrent ischemic strokes
Time Frame: at Day 10-14
The incidence rate of symptomatic or asymptomatic recurrent ischemic strokes on DWI
at Day 10-14

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Recurrent ischemic lesions
Time Frame: until Day 10-14

The incidence rate of recurrent ischemic lesions with significant clinical worsening (≥NIHSS 4)

The National Institutes of Health Stroke Scale, or NIH Stroke Scale (NIHSS) is a tool used by healthcare providers to objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the minimum score being a 0.
until Day 10-14
Clinical neurological deterioration
Time Frame: until Day 10-14

The rate of clinical neurological deterioration, rapid worsening of an existing focal neurological deficit (≥ 24 hours) that is clinically judged by the investigator not to be attributable to non-ischemic etiology (≥NIHSS 2)

The National Institutes of Health Stroke Scale, or NIH Stroke Scale (NIHSS) is a tool used by healthcare providers to objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the minimum score being a 0.
until Day 10-14
recanalization (full or partial) of occluded vessels
Time Frame: at Day 10-14
The rate of recanalization (full or partial) of occluded vessels on follow-up intracranial TOF
at Day 10-14
intracranial hemorrhages
Time Frame: at Day 10-14
The incidence rate of intracranial hemorrhages on follow-up gradient echo (GRE)
at Day 10-14
Functional status
Time Frame: at 3 months

Functional status (modified Rankin Scale [mRS])

The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability.

The scale runs from 0-6, running from perfect health without symptoms to death. 0 - No symptoms.

  1. - No significant disability. Able to carry out all usual activities, despite some symptoms.
  2. - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.
  3. - Moderate disability. Requires some help, but able to walk unassisted.
  4. - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.
  5. - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.
  6. - Dead.
at 3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Jong Sung Kim

Collaborators

Dong-A University Hospital
Soon Chun Hyang University
Kyung Hee University Hospital

Investigators

  • Principal Investigator: Jong Sung Kim, M.D.,Ph D., Asan Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 19, 2018

Primary Completion (Actual)

April 14, 2020

Study Completion (Actual)

July 2, 2020

Study Registration Dates

First Submitted

February 8, 2018

First Submitted That Met QC Criteria

February 8, 2018

First Posted (Actual)

February 14, 2018

Study Record Updates

Last Update Posted (Actual)

December 11, 2020

Last Update Submitted That Met QC Criteria

December 9, 2020

Last Verified

December 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AMC 2018-0033

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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